The present invention relates to riminophenazines having heteroaromatic substitutions, to their preparation, and to their use as drugs for treating Mycobacterium tuberculosis and other microbial infections, either alone or in combination with other anti-infective treatments.
Mycobacterium tuberculosis (“M.tb”) is the causative agent of tuberculosis (“TB”), a devastating infectious disease. It is estimated that about 2 million TB patients die each year globally. There are urgent needs for new drugs to fight the increasing threat of tuberculosis.
Current first-line drug therapy for tuberculosis is long and complex, involving multidrug combinations (usually isoniazid, rifampin, pyrazinamide and ethambutol) given daily for 6 to 9 months. Furthermore, these drugs are relatively ineffective against the resistant form of the disease and difficult to use to treat TB/HIV co-infected patients due to drug-drug interactions (Ma et al., 2009).
Clofazimine was first reported in 1957 by Barry and was found to possess potent antituberculosis activity (Barry, V. C., 1957). It demonstrated in vivo anti-TB activity in mice and hamsters, but failed to show efficacy in guinea pig and monkey models. The major drawbacks of clofazimine are skin discoloration, high fat tissue distribution, and very long half-life (70 days). New riminophenazine analogues have been synthesized to identify compounds with improved activity, lower side effects, and better solubility. Among those compounds, B4154 and B4157 showed improved in vitro activity (V. M. Reddy, 1996).
The structures of clofazimine, B4154, and B4157 are shown below.

One of the major advantages of the riminophenazine class is their low frequency for resistance development. They are highly potent against various forms of drug-resistant TB. New and improved riminophenazines could potentially contribute to the treatment of both drug-susceptible and drug-resistant tuberculosis.